Cancer Spectrum and Gene-Specific Patterns in Lynch Syndrome: Insights From 47 Families in a Brazilian Institutional...

To characterize tumor-site distribution, age at diagnosis, sex distribution, and tumor multiplicity in a Brazilian institutional Lynch syndrome (LS) cohort stratified by mismatch repair (MMR) gene and genetic testing status, and to assess the impact of including nontested (NT) relatives.

We conducted a retrospective, registry-based family cohort study of families ascertained in 2013-2019 with pathogenic or likely pathogenic variants in MLH1, MSH2, MSH6, PMS2, or EPCAM. For each proband, pedigree enumeration was limited to one cancer-enriched parental lineage. Adults (≥18 years) were included for tumor-site analyses. Relatives were classified as carriers (genotype-confirmed), noncarriers, or NT. Only primary malignant tumors were counted. Outcomes were any primary malignancy, multiplicity (≥2 primaries), age at first primary, and gene-specific tumor profiles summarized per person and per tumor.

Forty-seven families comprised 729 relatives; 111 (15.2%) underwent testing, identifying 78 carriers. Cohort composition was 78 (10.7%) carriers, 33 (4.5%) noncarriers, and 618 (84.8%) NT. Carriers were more often affected (≥1 tumor: 64.1% v 37.9% NT v 18.2% noncarriers), younger at first cancer (mean 42.3 v 47.3 years in NT), and more likely to have multiple primaries. Colorectal cancer predominated across genes; endometrial tumors were more frequent in MLH1/MSH2, and urothelial tumors clustered in MSH2 (descriptive). After false discovery rate control across LS-spectrum sites, site-wise multigene contrasts were not significant.

Carriers showed earlier onset and higher multiplicity, with gene-linked patterns consistent with LS heterogeneity. Low testing uptake broadened observed spectra among NT relatives, supporting cascade testing and genotype-tailored surveillance.